Our EDRN-CVC aims to improve prostate cancer detection. In our first funding cycle, we collected blood specimens from 1811 men before biopsy and led 2 EDRN-wide prostate cancer studies:1) The EDRN Prostate Cancer Blood Specimen Reference Set (>40,000 blood specimen aliquots shipped to the NCI) collected before biopsy in 669 men with or without prostate cancer (69% of the cohort was accrued at our CVC); cohort quality was verified by Hopkins BRL that used 3000 of the aliquots in proPSA validation study paving the way for FDA registration; 2) The EDRN Urine PCA3 trial at 10 clinical sites to test PCA3 prediction of prostate cancer and establish a Prostate Cancer Urine Reference Set at NCI-Frederick. Collaborating with LaBaer's BLD, we evaluated prostate cancer auto-antibodies but found their prevalence too low for clinical impact. After the Chinnaiyan BDL discovered TMPRSS2:ERG fusion (T-erg) we shifted focus: Our CVC Pathologist developed a FISH assay we used to detect T-erg fusion in 46% prostate cancers on biopsy, and in a Swedish cohort showed fusion association with lethal progression. Our CVC enabled assays to detect T-erg in urine collected after DRE, and we combined urine T-erg, PCA3 and serum PSA to outperform PSA alone in predicting cancer (AUC 0.75 vs .58). We hypothesize that T-erg detection can mitigate problems of PSA screening. We propose: 1) To prospectively validate the performance of urinary Terg in a multiplex model predicting prostate cancer diagnosis in 900 men with post-DRE urine collected prior to prostate biopsy. 2) To determine T-erg prevalence among African-American men in a community-based sample of 840 men (including 420 African Americans) in a community outreach men's health initiative. 3) To compare accuracy of detecting T-erg in post-DRE urine to detecting the fusion by biopsy FISH. 4) To test if Terg discerns longitudinally progressive from indolent cancer in 300 men on active surveillance at our CVC, and bring to EDRN prostate biopsy tissue from a national cohort of 300 men who deferred treatment (from Health Professionals Follow-up Study) for Phase II validation. 5) To Collaborate with BDLs, BRLs, CVCs to evaluate and validate other new protein, RNA and SNP biomarkers of prostate cancer.